Peripheral nerve grafting is an important clinical procedure for the restoration of nerve function after trauma that creates a gap between injured nerve ends. We have previously reported that nerve allografts can be used to repair a long gap in a nerve, but only if the recipient is chronically immunosuppressed with the drug Cyclosporin A (Cy-A). Cy-A therapy cannot be stopped since nerve rejection occurs and host axons that traverse the graft degenerate. It is puzzling why kidney and heart allografts survive indefinitely after stopping Cy-A treatment whereas nerve allografts are rejected. In order to help resolve this problem we performed an experiment with nerve allografts in which we used the same Cy-A treatment protocol and rat strains used by others to induce permanent survival of heart allografts. DA peroneal nerve grafts (4 cm long) were bilaterally grafted into the legs of PVG recipients that were given Cy-A(15mg/kg, intramuscularly) according to the following schedule: Cy-A for 1 week beginning the day of surgery followed by 2 weeks off the drug, then another week of treatment and a second two weeks off Cy-A and finally by a 3 day boost of Cy-A with no further treatment. We found that untreated PVG rats rejected DA nerve grafts by 28 days. On the other hand, DA nerves survived in Cy-A-treated PVG recipients at 63 days, the last period of observation. Since only one DA nerve was removed from various immunosuppressed PVG rats, we plan to wait until 100 days and regraft these rats with a new DA or ACI rat nerves. If the Cy-A treatment described induces donor-specific graft tolerance (i.e., long- term graft acceptance), as proposed by others, then the second as well as the original DA nerves should survive whereas the ACI graft should be rejected. We are encouraged to believe that for the first time a model of tolerance induction to nerve allografts will be achieved with short- term drug immunosuppression. In another experiment we used the electron microscope to determine the long-term fate of Schwann cell basement membrane (SCBM) in rejected nerve allografts. Some investigators believe that SCBM tubes alone might support host nerve fiber growth. This notion assumes that SCBM persists as tubes indefinitely. We found that SCBM collapsed and became fragmented at 4 weeks, a time at which all allogeneic cells were rejected. From 4-8 weeks postoperatively, SCBM gradually disappeared or remained as small irregular patches. Moreover, host axons and Schwann cells grew only 1-2 cm into the 6 cm long allografts. The degradation of SCBM tubes implies that only a short gap in an injured nerve can be repaired with an acellular graft.